Project Summary The primary focus of managing type 2 diabetes (T2D) has traditionally been the strict control of blood glucose using one or multiple orally administered medications. Drugs currently used to treat T2D range from pharmaceutical agents that increase insulin secretion or sensitivity, to those that decrease hepatic gluconeogenesis or intestinal carbohydrate absorption. Agents that are more recent include glucagon-like peptide-1 (GLP-1) analogues, which inhibit the breakdown of endogenous GLP-1 by dipeptidyl peptidase-IV (DPP-IV), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, which block normal glucose reabsorption in the kidneys. According to the United Kingdom Prospective Diabetes Study (UKPDS 33), even though the efficacy of these drugs in preventing microvascular complications of T2D (e.g., retinopathy, neuropathy and nephropathy) has been partially established, their role in preventing macrovascular complications (e.g., coronary heart disease and stroke) remains elusive. Moreover, the same study points out that 50 percent of patients originally controlled with a single drug acquired tolerance and needed the addition of a second drug after three years, and by nine years, about 75 percent of patients needed multiple therapies to achieve the target HbA1c value. There is significant evidence that in some T2D patients, despite taking medications, the ?-cell function undergoes continuous decline and eventually fails entirely, leaving these patients the only option of insulin therapy. Rather than being used as a treatment of last resort however, the clinical and research communities are recognizing that early initiation of insulin therapy in T2D patients will correct all of the underlying pathogenic mechanisms such as increased ?-cell apoptosis, glucotoxicity, lipotoxicity, and inflammation. Major drawbacks of early insulin injections for T2D include risks of cardiovascular disease, weight gain and hypoglycemia, stemming from irregular or incorrect dosing, lack of time in the physician's schedule to manage insulin therapy, and most importantly, patient non-compliance. Successful oral delivery of insulin is therefore a therapeutic Holy Grail as its inherent ease of administration mimicking natural secretion process potentially obviates or minimizes many of the drawbacks, and should reduce much of the burden of managing T2D by health care professionals. However, gastric instability and lack of transport across tightly packed epithelium and overlying mucus are formidable challenges to successful intestinal absorption of insulin. The work enabled by previous findings, in which oral delivery of insulin using ligand-directed nanoparticles that do not compete with physiological ligands led to improved therapeutic outcomes compared to conventional nanoparticles. In this project, the technology is further developed by investigating, how fine-tuning the nanoparticle composition affect the drug disposition and therapeutic outcomes, under the influence of commonly experienced physiological and pathophysiology conditions. In doing so, the project will establish 1) optimal non-competitive nanoparticle chemistry, 2) active drug delivery under pertinent physiological conditions, and 3) the therapeutic window of oral insulin in T2D.